Changes in cardiovascular-health blood biomarkers in response to exercise intervention among older adults with cognitive frailty: A scoping review

Introduction: Cardiovascular health contributes significantly to the incidence of cognitive impairment. Prior to conducting exercise-related intervention, it is crucial to explore cardiovascular health blood parameters that have been commonly used as guidance for the purpose of monitoring. Information on the effectiveness of exercise on cardiovascular-related biomarkers is lacking, especially among older adults with cognitive frailty. Therefore, we aimed to review existing evidence on cardiovascular-related blood parameters and their changes following exercise intervention among older adults with cognitive frailty. Methods: A systematic search was conducted on PubMed, Cochrane, and Scopus databases. Related studies involving only human and full text in either English or Malay language were selected. Types of impairment were limited to cognitive impairment, frailty, and cognitive frailty. Studies were restricted to randomized controlled trial and clinical trial design studies. For charting purposes, all variables were extracted and tabulated. Trends in types of parameters studied were explored. Results: A total of 607 articles were screened, and the final 16 were included in this review. Four cardiovascular-related blood parameter categories were extracted: inflammatory, glucose homeostasis, lipid profile, and hemostatic biomarkers. The common parameters monitored were IGF-1 and HbA1c, glucose, and insulin sensitivity in some studies. Out of the nine studies on inflammatory biomarkers, exercise interventions showed a reduction in pro-inflammatory markers, namely, IL-6, TNF-α, IL-15, leptin, and C-reactive protein and an increase in anti-inflammatory markers, namely, IFN-γ and IL-10. Similarly, in all eight studies, glucose homeostasis-related biomarkers had improved with exercise intervention. The lipid profile was tested in five studies, with four studies showing improvements with exercise intervention via a decrease in total cholesterol, triglycerides, and low-density lipoprotein and an increase in high-density lipoprotein. A decrease in pro-inflammatory biomarkers and an increase in anti-inflammatory biomarkers were demonstrated with multicomponent exercise, including aerobic exercise in six studies and aerobic exercise on its own in the remaining two studies. Meanwhile, four out of six studies that yielded improvements in glucose homeostasis biomarkers involved only aerobic exercise and the remaining two studies involved multicomponent with aerobic exercise. Conclusion: The most consistent blood parameters studied were glucose homeostasis and inflammatory biomarkers. These parameters have been shown to improve with multicomponent exercise programs, particularly with the inclusion of aerobic exercise.


Introduction
Cognitive frailty is a significant predictor of dementia (Bu et al., 2021). This is signified by cognitive impairment and physical frailty, according to the definition provided by the International Academy on Nutrition and Aging and the International Association of Gerontology and Geriatrics (Kelaiditi et al., 2013). Cardiovascular health (CVH) has been consistently identified as a dementia risk factor, and most importantly, it is one of the modifiable risk factor (Livingston et al., 2020;Wu et al., 2022). CVH is the health of heart and blood indicated by smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose and blood parameter and is a consistent and sensitive outcome measure for changes in CVH (Lloyd-Jones et al., 2010).
Most of the studies have utilized lipid profile (total serum cholesterol and triglycerides), glucose homeostasis (glucose and hemoglobin A1c), and hemostatic markers (hemoglobin and homocysteine) to assess CVH as a risk factor among older adults with dementia or cognitive impairment (Samieri et al., 2018;Peters et al., 2019). On the effectiveness of intervention, the review by Lin et al. (2015) on unspecified adults reported that exercise improved lipid profiles, glucose metabolism, and anti-inflammatory markers. On the contrary, the effectiveness of exercise on CVH-related blood parameters among 1,567 healthy older adults with three-arm intervention using high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), triglycerides (TG), hemoglobin A1c (HbA1c), and glucose did not show any changes or improvements (Letnes et al., 2022). Almost similar systematic reviews dated until March 2014 have been conducted on general adults without age limit and impairment. There is a lack of information on the effectiveness of exercise on cardiovascular-related biomarkers, particularly among older adults with cognitive frailty (CF).
Therefore, this review aimed to scope the information on cardiovascular-related blood parameters among older adults with CF in response to exercise intervention. This will aid in the identification and choice of cardiovascular-related blood parameters to be assessed as changes in CVH with exercise intervention. This syndrome, CF, is a probable precursor to negative health-related consequences, namely, falling, injuries, and disability among older adults (Rivan et al., 2021;Richter et al., 2022).

Methods
This scoping review was prepared based on the Arksey and Malley (2007) framework. Our protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis protocol for scoping reviews (PRISMA-ScR) (Tricco et al., 2018). All methods were uploaded on the Open Science Framework (Ibrahim, 2020).

Stage 1: Identify the research question
The research questions addressed in this study were: what are the cardiovascular-health biomarkers that have been studied among older adults with cognitive frailty who underwent exercise intervention? Second, which type of exercise intervention yields changes in cardiovascular-health biomarkers upon intervention among older adults with cognitive frailty? Both single exercise interventions and multicomponent interventions were included. Due to the availability of the limited number of studies related to this area, older adults with cognitive frailty and cognitive impairment or a frail population was included in this review.

Stage 2: Identify relevant studies
We used the mnemonic PCC: population, context, and concept in Table 1 as a guide for identifying the relevant studies, particularly those focused on cardiovascular-health blood biomarkers among older adults with cognitive frailty who undertook exercise intervention. PubMed, Cochrane, and Scopus were used to search for peer-reviewed studies published in English and Malay.
A combination of keywords and MeSH terms were used based on the theme of the research questions. The following keywords were used: 1. Exercise OR "physical activity" OR "physical exercise*" OR aerobic OR endurance OR Strength* OR "exercise training*" OR "strength training." 2. "Older adult" OR old* OR elderly OR geriatric. 3. "Cognitive frail*" OR frail* OR "cognitive impairment" OR "mild cognitive impairment." 4. Biomarkers OR biochemical OR "marker" OR "biological marker" OR "clinical marker" OR laboratory OR "bio-indicator." 5. Randomized control* trial OR randomized controlled trial OR controlled clinical trial OR random allocation OR intervention studies.

Stage 3: Study selection
The inclusion criteria were full peer-reviewed, journal articles in English or Malay language, an age limit of 60 and above, and a randomized controlled trial study design in which participants with Frontiers in Physiology frontiersin.org 02 cognitive impairment, frailty, or cognitive frailty were assigned to at least one group of participants for exercise and in which cardiovascularrelated blood biomarkers among older adults were examined. We excluded articles based on one or more of the following reasons: study subjects were not human, pediatric population, and duplicate and/or unrelated study topic. To establish the protocol for determining eligibility, two content experts AI and AFML reviewed the title and abstracts. Once reviewers established that the selected articles met the eligibility criteria and full consensus, the criteria for article identification and inclusion were applied. The Rayyan platform was used for screening purposes (Ouzzani et al., 2017).

Stage 4: Charting the data
The following information was extracted from every eligible record: author(s), year of publication, age, sex, body mass index, duration of exercise intervention, details of exercise, type of biomarker, and changes in biomarker.

Stage 5: Collating, summarizing, and reporting results
Once the eligible studies were extracted, we developed an analytical framework to collate, summarize, and synthesize the data. We made use of summary counts and tables to provide quantitative information on the body of research on blood biomarkers studied in the aforementioned population.

Selection of included studies
After screening for the keywords, a total of 607 articles were gathered from the three selected databases. Upon duplicate removal, 348 articles were screened for titles and abstracts. Following that, 28 articles were selected for full-text screening. Finally, a total of 16 articles were selected for data extraction ( Figure 1).

Population
Older person with cognitive impairment, frailty, or cognitive frailty

Cardiovascular biomarker
Context Exercise intervention

FIGURE 1
Syntax of literature search and selection process. PRISMA flow diagram: cardiovascular-health biomarkers in intervening older adults with cognitive frailty.

General characteristics of included studies
All included studies were randomized controlled trials, while the intervention period varied from 12 to 96 weeks. These studies were published between 1999 and April 2022, and included both sexes and impairments, including frailty (n = 7) and cognitive impairment (n = 9), as depicted in Table 2.
Out of 16 studies, there were five single-component intervention (exercise alone) studies that employed single type of exercise in an arm (aerobics, resistance, tai chi, and HIIT). Another three studies combined more than one type of exercises in an arm [aerobics + resistance (n = 1) and aerobics + resistance + balance (n = 2)]. There were a total of eight multicomponent intervention studies [exercise + diet (n = 3), exercise + supplementation (n = 4), and exercise + diet + vascular management + cognitive training (n = 1)].

Common type of biomarkers studied
In view of cardiovascular health-related biomarkers in response to exercise, most of the articles included inflammatory (n = 9), followed by glucose homeostasis (n = 9), lipid profile markers (n = 5), and hemostatic factors (n = 1) ( Table 3).
Only one study by Köbe et al., 2016 reported on the hemostatic factor, homocysteine. This study indicated a reduction in homocysteine with exercise intervention in combination with other interventions.
Seven out of the eight studies included aerobic exercise on its own (Baker et al., 2010;Köbe et al., 2016;Tsai et al., 2018;Smith et al., 2020) and as part of multicomponent exercise (Ferreira et al., 2018;Tsai et al., 2019;Koblinsky et al., 2022). They showed improvement in glucose metabolism via various parameters, including Hba1c, HOMA-IR, IGF-1, and glucose disposal via metabolic clamp. Only one study carried out a comparison between aerobic and resistance exercises, and the results showed that aerobic exercise reduced the insulin level, while resistance exercise increased the IGF-1 level (Tsai et al., 2019). Baker et al. (2010) compared aerobic and stretching exercises among 33 older populations with MCI. These authors found that high-intensity aerobic exercise significantly improved glucose disposal during metabolic clamp, insulin sensitivity, and BDNF among women. Meanwhile, for men, aerobic exercise improved IGF-1.
Concerning body fat, the total body fat was reduced in both men and women in aerobic groups, while the total cholesterol  n T, sample size of the treatment group; n C, sample size of the control group; MPO, myeloperoxidase; IL-6, interleukin 6, BDNF, brain-derived neurotrophic factor; CRP, C-reactive protein.
Frontiers in Physiology frontiersin.org 08 significantly reduced with aerobic exercise (Baker et al., 2021) but increased in the stretching group (Baker et al., 2010). LDL was found to have an analogous pattern but not HDL and triglycerides.
In the four studies that have yielded improvements in the lipid profile, only two studies carried out aerobic exercise (Köbe et al., 2016;Baker et al., 2021). On the other hand, the other two aerobic exercises were performed in combination with the resistance and balance exercises (Stephen et al., 2021) or resistance exercise, mobility, and flexibility (Ferreira et al., 2018). With regard to single-component exercise, aerobic exercise among patients with MCI significantly reduced their homocysteine and triglyceride values (Köbe et al., 2016). Improvement trends in several parameters, namely, leptin, IGF-1, total cholesterol, LDL/HDL ratio, and BDNF level were also found. Second, in the study by Furtado et al. (2020), multimodal chair-based and chair-based exercises with the elastic band were compared. The results found that there was an increase in IL-10 and decrease in IFN.

Key findings
In this scoping review, we mapped changes in cardiovascular health-related blood parameters among older adults with cognitive frailty in response to exercise on its own or as a component of the intervention. To the best of our knowledge, this is the first review covering the impact of exercise intervention on older adults with cognitive frailty. The overall results showed that the cardiovascular health-related biomarkers studied were mostly inflammatory, glucose-metabolism-related, and lipid profile markers.
Among all the inflammatory parameters, a reduction was observed in TNF-α (Tsai et al., 2019;Sungkarat et al., 2018;Furtado et al., 2020) and leptin (Köbe et al., 2016;Smith et al., 2020). The increase in TNF-α in the study by Caldo-Silva et al. (2021) could be due to the higher comorbidity index and lower cognitive profile. In addition, leptin decreased in response to aerobic exercise intervention (Köbe et al., 2016;Smith et al., 2020). Leptin stimulates fatty acid oxidation while decreasing incorporation of fatty acid into intramuscular lipid droplets. Ageing process can be described with low-grade chronic inflammation, leading to muscle loss. Previous studies have shown that multicomponent exercise is more effective in improving inflammatory markers (Sadjapong et al., 2020). Inflammatory markers, such as CRP, IL-6, and TNF-α, were reported as stable and least likely to be affected by exercise behavior (Che and Li, 2017). Cardiovascular biomarkers were also categorized based on inflammatory factors, functional metabolomics, and heart-specific proteome (Che and Li, 2017). However, the response to exercise on the stated biomarkers was scarce.
In view of the type of exercise that exerted anti-inflammatory effects, three studies using multicomponent exercise showed positive changes in anti-inflammatory biomarkers (Ferreira et al., 2018;Guilherme et al., 2020;Caldo-Silva et al., 2021). In a recent systematic review that determined the effectiveness of aerobic exercises on inflammatory markers in healthy middle-aged and older adults, positive changes in inflammatory markers were reported (Zheng et al., 2019).
In our present review, we found that multicomponent exercises led to positive changes in anti-inflammatory biomarkers among older adults with cognitive impairment and frailty. This could be due to the fact that multicomponent exercises are beneficial to addressing many associated issues related to both cognitive impairment and physical frailty, such as weakness, impaired postural stability, fear of falling, and quality of life. As a result, there is holistic improvement in physical and psychosocial health. This is further supported by evidence that multicomponent exercise interventions are beneficial to the prevention and reversal of cognitive impairment and/or frailty Sáez de Asteasu et al., 2019;Kim et al., 2020;Murukesu et al., 2020;Murukesu et al., 2021).
An increase in age is associated with glucose intolerance and insulin resistance. With skeletal muscle being the main target for glucose uptake, the structural and metabolic changes of this tissue associated with ageing has a significant role in pathogenesis of insulin resistance in the ageing population. Myriad benefits of aerobic exercise on glucose metabolism can be explained via improved skeletal muscle insulin signaling factor (AS160), GLUT4 protein content, and glycogen synthase and oxidative (PDH). These changes are similar to those by resistance exercise except that there is limited improvement in skeletal muscle GLUT4 and insulin-stimulated glycogen synthase pathways (Consitt et al., 2019).
A reduction in total cholesterol among participants in all four studies (Baker et al., 2010;Köbe et al., 2016;Roschel et al., 2021;Stephen et al., 2021) is also supported by the study by Da Silva et al. (2016). These can be explained by the increase in the activity of lipase lipoprotein and lecithin cholesterol acyltransferase and the reduced activity of hepatic lipase and cholesterol esterified transfer protein which reverses cholesterol transport (Lehmann et al., 2001;Da Silva et al., 2016).

Research Gaps
There is limited research regarding the effectiveness of exercise on cardiovascular health-related parameters among older adults with cognitive impairment or frailty, especially cognitive frailty. More information is required pertaining to this matter to assist in designing the best evidence-based exercise program in the prevention and management of cognitive frailty in older adults.

Study limitations
This review reported important findings. However, several limitations should be acknowledged. First, the quality appraisal of studies was not assessed. Second, three databases were accessed. Although it is adequate, using more databases may allow a better understanding.

Conclusion
In the present review, we found that exercise intervention yielded positive outcomes in cardiovascular health-related biomarkers, particularly pro-inflammatory markers, namely, IL-6, TNF-α, IL-15, leptin, and C-reactive protein and anti-inflammatory markers, namely, Frontiers in Physiology frontiersin.org 09 IFN-γ and IL-10. Similarly, glucose metabolism-related biomarkers, namely, IGF-1 and HbA1c, glucose, and insulin sensitivity were shown to be improved with exercise intervention. Most studies, which showed improved biomarker outcomes, were in response to multicomponent exercise (combination of aerobic, resistance, flexibility, and balance exercises) and only aerobic exercise.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author.